Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational Exposure and Congenital Malformation Working Group

OBJECTIVES: This study examined the relationship between maternal tobacco and alcohol consumption during the first trimester of pregnancy and oral clefts. METHODS: Data were derived from a European multicenter case-control study including 161 infants with oral clefts and 1134 control infants. RESULTS: Multivariate analyses showed an increased risk of cleft lip with or without cleft palate associated with smoking (odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.07, 3.04) and an increased risk of cleft palate associated with alcohol consumption (OR = 2.28, 95% CI = 1.02, 5.09). The former risk increased with the number of cigarettes smoked. CONCLUSIONS: This study provides further evidence of the possible role of prevalent environmental exposures such as tobacco and alcohol in the etiology of oral clefts.     

Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns.

The results of previous epidemiologic research on the possible association between maternal smoking during pregnancy and risk of oral clefts in offspring have been inconsistent. This may be due in part to methodological limitations, including imprecise measurement of tobacco use, failure to consider etiologic heterogeneity among types of oral clefts, and confounding. This analysis, based on a large case-control study, further evaluated the effect of first trimester maternal smoking on oral facial cleft risk by examining the dose-response relationship according to specific cleft type and according to whether or not additional malformations were present. A number of factors, including dietary and supplemental folate intake and family history of clefts, were evaluated as potential confounders and effect modifiers. Data on 3,774 mothers interviewed between 1976 and 1992 by the Slone Epidemiology Unit Birth Defects Study were used. Study subjects were actively ascertained from sites in areas around Boston, Massachusetts and Philadelphia, Pennsylvania; the state of Iowa; and southeastern Ontario, Canada. Cases were infants with isolated defects--cleft lip alone (n = 334), cleft lip and palate (n = 494), or cleft palate alone (n = 244)--and infants with clefts plus (+) additional malformations: cleft lip+ (n = 58), cleft lip and palate+ (n = 140), or cleft palate+ (n = 209). Controls were infants with defects other than clefts, excluding defects possibly associated with maternal cigarette use. There were no associations with maternal smoking for any oral cleft group, except for a positive dose response among infants with cleft lip and palate+ (for light smokers, odds ratio (OR) = 1.09 (95% confidence interval (CI): 0.6, 1.9); for moderate smokers, OR = 1.84 (95% CI: 1.2, 2.9); and for heavy smokers, OR = 1.85 (95% CI: 1.0, 3.5), relative to nonsmokers). This finding may be related to the additional malformations rather than to the cleft itself.     

Congenital malformations and maternal occupation: a registry based case-control study.

OBJECTIVES: To investigate the relations between congenital malformations and maternal occupation during pregnancy with a registry based case-control study. METHODS: Analysis was performed on data derived from the Florence Eurocat registry surveillance programme. The study included cases with isolated conditions, including chromosomal anomalies (n = 1351), cases with multiple anomalies registered during the 1980-91 period (n = 440), and babies with no congenital malformations recognised at birth who were born from 1982 to 1989 and selected as controls (n = 3223). 11 categories were defined, 10 including cases with isolated malformations and one for cases with multiple congenital anomalies. Four categories of maternal occupation were selected for the study. Odds ratio (OR) values were adjusted for maternal origin, maternal and paternal education, number of previous live births, illness during pregnancy, and maternal age when the group of chromosomal anomalies was analysed. RESULTS: A notable and significant association between oral clefts and mothers involved in leather and shoe manufacturing was found (adjusted OR 3.9; 99% confidence interval (99% CI) 1.5 to 9.8) and the risk consistently increased when considering cases with isolated cleft palate separately (OR 5.4; 95% CI 1.8 to 13.4). Moreover, a significant risk was identified for the association between multiple anomalies and textile dye workers (adjusted OR 1.9; 99% CI 1.0 to 3.8). CONCLUSIONS: This study indicates a notable, significant relation between maternal occupation as a pelt or leather worker and orofacial clefts in offspring. This finding is in agreement with the suggested inheritance models. The dilution effect due to studying large and heterogeneous groups of workers and occupations limits the value of the study; but it provides a good example of the use of a large database to search for teratogenic risk with the aid of malformation registries.     

Parent's occupation and isolated orofacial clefts in Norway: a population-based case-control study

PURPOSE: Occupational factors have been associated with risk of orofacial clefts in offspring, although data are limited. We explored associations between parent's occupation and isolated orofacial clefts using a population-based case-control study. METHODS: Cases were restricted to infants born with an isolated orofacial cleft in Norway during the period 1996 to 2001 (314 with cleft lip with or without palate [CLP] and 118 with cleft palate only [CPO]). Controls (n = 763) were chosen randomly from all Norwegian live births. We considered full-time employment during the first 3 months of pregnancy. RESULTS: Several maternal occupations previously associated with clefts showed some evidence of association, including hairdressers (CLP; adjusted odds ratio = 4.8; 95% confidence interval [CI]: 0.99-23). Mothers working in manufacturing and in food production had increased odds for babies with CPO (3.8; 1.3-11, and 7.1; 1.5-33, respectively). Among fathers' occupations previously associated with clefts, an association was suggested for woodworking both for CLP (1.7; 0.85-3.2) and for CPO (2.0; 0.82-4.7). Fathers working as professional housekeepers showed substantial increased odds of CPO (12; 3.3-46). CONCLUSIONS: Taken together with previous studies, these results suggest that exposures in certain occupations may influence the risk of orofacial clefting in offspring. Specific exposures accompanying these occupations warrant exploration.     

Maternal cigarette smoking during pregnancy in relation to oral clefts

Studies on maternal smoking in relation to oral cleft defects have yielded inconsistent findings, with results ranging from no association to sixfold increases in risk. The authors examined this relation in a case-control study conducted in Boston, Massachusetts, Philadelphia, Pennsylvania, Toronto, Ontario, Canada, and the state of Iowa during the years 1983-1987, in which mothers of malformed infants were interviewed within 6 months after delivery about prenatal events and exposures. Maternal cigarette smoking during pregnancy for 400 infants with cleft lip with or without cleft palate and for 215 infants with cleft palate alone was compared with that for 2,710 infants with other malformations (controls). Relative risks (and 95% confidence intervals) were estimated for smokers of 1-14, 15-24, and greater than or equal to 25 cigarettes per day relative to never smokers; the respective estimates for cleft lip with or without cleft palate were 1.2 (95% confidence interval (CI) 0.9-1.6), 1.4 (95% CI 1.0-2.1), and 0.7 (95% CI 0.3-1.6), and for cleft palate alone, estimates were 1.0 (95% CI 0.7-1.5), 0.9 (95% CI 0.5-1.5), and 0.8 (95% CI 0.3-2.2). Relative risks were also close to unity for case subgroups divided according to the presence or absence of an associated malformation. Multivariate control of several potential confounders did not alter these estimates. Based on this large series of cases, maternal smoking during pregnancy does not appear to increase the risk of oral clefts.     

Parental occupational pesticide exposure and nonsyndromic orofacial clefts

Nonsyndromic orofacial clefts are common birth defects. Reported risks for orofacial clefts associated with parental occupational pesticide exposure are mixed. To examine the role of parental pesticide exposure in orofacial cleft development in offspring, this study compared population-based case-control data for parental occupational exposures to insecticides, herbicides, and fungicides, alone or in combinations, during maternal (1 month before through 3 months after conception) and paternal (3 months before through 3 months after conception) critical exposure periods between orofacial cleft cases and unaffected controls. Multivariable logistic regression was used to estimate odds ratios, adjusted for relevant covariables, and 95% confidence intervals for any (yes, no) and cumulative (none, low [相似文献   

Spontaneous abortion and maternal work in greenhouses

BACKGROUND: A positive association between maternal occupational exposure to pesticide and spontaneous abortion has been reported in some studies. Work in greenhouses may imply exposure of pregnant women to pesticides continuously and at elevated level. METHODS: A total of 717 women working in greenhouses provided information on 973 pregnancies, including 110 spontaneous abortions. These pregnancies were classified as exposed or not exposed according to maternal occupation, re-entry activities and application of pesticides in greenhouses during at least 1 month in the first trimester of pregnancy. The ORs for spontaneous abortion were estimated through a generalised estimate equations model for all orders of pregnancy together, and through a logistic regression model limited to first pregnancies. RESULTS: Increased risks of spontaneous abortion were found for maternal re-entry activities within 24 hr after pesticides were applied (all orders of pregnancy: OR 3.2, 95% CI 1.3-7.7; first pregnancies: OR 3.8, 95% CI 1.0-13.9) and for those who applied pesticides (all orders of pregnancy: OR 2.6, 95% CI 1.0-6.6; first pregnancies: OR 3.7, 95% CI 0.7-20,6) CONCLUSIONS: The observed results support the hypothesis of an association between maternal work in greenhouses and spontaneous abortion. The main limitations of the study are lack of information on the specific chemicals used and the small number of pregnancies heavily exposed to pesticides.     

先天性泌尿生殖系统结构畸形危险因素的研究

目的：探讨有关因素在先天性泌尿生系统结构畸形发病中的作用。方法：采用成组匹配的病列对照研究方法。对95例患先天性泌尿生殖系统 的围产儿和160例对照围产儿及其父母的情况进行调查。采用非条件logistic回归模型进行多因素分析,计算OR值及OR的95％可信限。结果：先天性泌尿生殖系统结构畸形多发生于男性围产儿（性别成比为74．7％,X^2＝74．863,P＝0．001）,多元逐步回归分析表明：母亲孕早、中期感冒（OR＝7．034,95％CI＝3．488－14．187）、低出生体重（OR＝4．075,95％CI＝1．774－9．362）、孕次≥2（OR＝3．133,95％CI＝1．514－6．483）及母亲孕前职业性接触有害化学物质（OR＝10．496,95％CI＝1．053－104．651）为先天性泌尿生殖系统结构畸形的危险因素,结论：胎儿男性别,母亲孕早、中期感冒、低出生体重,母亲孕次≥2及孕前职业性接触有害化学物质与胎儿发生先天性泌尿生系统畸形有关联。     

Tobacco smoking and oral clefts: a meta-analysis

OBJECTIVE: To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS: A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS: Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION: The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns.     

Interaction between smoking and body mass index and risk of oral clefts

PurposeTo examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts.MethodsWe studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors.ResultsWe found a significant negative smoking–BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39–1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34–1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22–1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04–1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92–1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only.ConclusionsOur findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking–BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women.     

Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts

Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.     

Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring.

To evaluate the effects of parental occupational chemical exposures on incidence of neuroblastoma in offspring, the authors conducted a multicenter case-control study, using detailed exposure information that allowed examination of specific chemicals. Cases were 538 children aged 19 years who were newly diagnosed with confirmed neuroblastoma in 1992-1994 and were registered at any of 139 participating hospitals in the United States and Canada. One age-matched control for each of 504 cases was selected through random digit dialing. Self-reported exposures were reviewed by an industrial hygienist, and improbable exposures were reclassified. Effect estimates were calculated using unconditional logistic regression, adjusting for child's age and maternal demographic factors. Maternal exposures to most chemicals were not associated with neuroblastoma. Paternal exposures to hydrocarbons such as diesel fuel (odds ratio (OR) = 1.5; 95% confidence interval (CI): 0.8, 2.6), lacquer thinner (OR = 3.5; 95% CI: 1.6, 7.8), and turpentine (OR = 10.4; 95% CI: 2.4, 44.8) were associated with an increased incidence of neuroblastoma, as were exposures to wood dust (OR = 1.5; 95% CI: 0.8, 2.8) and solders (OR = 2.6; 95% CI: 0.9, 7.1). The detailed exposure information available in this study has provided additional clues about the role of parental occupation as a risk factor for neuroblastoma.     

Maternal smoking and the risk of orofacial clefts: Susceptibility with NAT1 and NAT2 polymorphisms

BACKGROUND: Orofacial clefts are etiologically heterogeneous malformations. One probable cause is maternal smoking during pregnancy. The effect of maternal smoking may be modified by genes involved in biotransformation of toxic compounds derived from tobacco. We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft. METHODS: In a California population-based case-control study, we genotyped 421 infants born with an isolated cleft and 299 nonmal-formed controls for 2 NAT1 and 3 NAT2 single nucleotide polymorphisms RESULTS: Although smoking was independently associated with increased risks for both isolated cleft lip +/- cleft palate and isolated cleft palate, no independent associations were found for NAT1 1088 or 1095 genotypes or for NAT2 acetylator status. However, the infant NAT1 1088 and 1095 polymorphisms were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval = 1.1-17.2) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 1.2-18.0). Infant NAT2 acetylator status did not appreciably affect susceptibility of the fetus to the teratogenic effects of maternal smoking. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy may increase risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1, an enzyme involved in phase II detoxification of tobacco smoke constituents.     

Childhood leukemia and parental occupation. A register-based case-control study

To explore possible etiologic factors of childhood leukemia, a case-control study was performed in the Netherlands. Cases were selected from a complete nationwide register of cases of childhood leukemia which were diagnosed between 1973 and 1980. Controls were matched with cases for year of birth, sex, and place of residence at the time of diagnosis. Information about possible exposures was collected by a postal questionnaire addressed to the parents. This report concerns the results of the analysis of parental occupations and occupational exposures for 519 children with acute lymphocytic leukemia and 507 controls. During pregnancy, more mothers of patients were working in "hydrocarbon-related" occupations; relative risk (RR) = 2.5 (95% confidence interval (CI) = 0.7-9.4). Likewise, greater occupational exposure to chemicals (paint, petroleum products, and unspecified chemicals) during pregnancy was found for mothers of patients (RR = 2.4, 95% CI = 1.2-4.6). The kind of work being performed by the mothers one year before diagnosis did not differ between cases and controls. For the fathers, no relationship was found between a hydro-carbon-related occupation or occupational exposure to chemicals and leukemia in the offspring. Adjustment for birth order, social class, and degree of urbanization did not materially change the relative risks.     

Risk factors for oral clefts: a population-based case-control study in Shenyang, China

Shenyang in Northern China has one of the highest reported prevalence rates of oral clefts in the world. To explore the risk factors for oral clefts in Shenyang, we carried out a population-based case-control study. A total of 360 990 births in 2000 to 2007 were screened for oral clefts; the overall prevalence was 1.76 per 1000. The ratio of cleft lip with or without cleft palate (CL ± P) : cleft palate only (CP) was 5.60:1. The overall male : female ratio was 2.02:1. CLP and CL were more common in males than in females with a sex ratio (SR) of 2.88:1 and 1.86:1 respectively, whereas CP was more common in females with an SR of 0.71:1.
Using a multivariable conditional logistic regression model, 586 oral clefts cases were compared with 1172 control mothers. Maternal factors significantly associated with increased risk for oral clefts were history of a fever or cold (adjusted OR 2.34, 95% CI 1.06, 5.60); use of analgesic and antipyretic drugs (adjusted OR 3.10, 95% CI 1.41, 6.86); poor ventilation during heating (adjusted OR 2.25, 95% CI 1.10, 4.60); and consumption of pickled vegetables >6 per week (adjusted OR 3.86, 95% CI 1.11, 13.47) during pregnancy. Factors which appeared to be protective were meat consumption ≥4 times per week (adjusted OR 0.43, 95% CI 0.28, 0.67); and legume consumption >6 times per week (adjusted OR 0.60, 95% CI 0.41, 0.89). Differences in risk were found between the two most common phenotypes, CL ± P and CP only. Most of the environmental factors had stronger associations with risk for CL ± P rather than CP, whereas history of oral clefts, as well as legume consumption, were more strongly associated with the risk for CP than for CL ± P. The findings suggest that aetiological heterogeneity may exist between CL ± P and CP.     

Association of transposition of the great arteries in infants with maternal exposures to herbicides and rodenticides

The Baltimore-Washington Infant Study, a case-control study of congenital heart defects in liveborn infants conducted in 1981--1989, interviewed parents about a wide range of environmental exposures that occurred during and before the pregnancy. In the period 1987--1989, the questionnaire was expanded to include a detailed inquiry about exposures to pesticides. An analysis of these latter data revealed an association of maternal exposure to any pesticides during the first trimester with transposition of the great arteries in their infants (TGA; n = 66 infants), relative to 771 control infants, with an odds ratio of 2.0 (95% confidence interval (CI): 1.2, 3.3). No other heart defects were associated with pesticides. When analyzed by type of pesticide and adjusted for covariates, there were associations of TGA with maternal exposures to herbicides (odds ratio (OR) = 2.8; 95% CI: 1.3, 7.2) and to rodenticidal chemicals (OR = 4.7; 95% CI: 1.4, 12.1) but not to insecticides (OR = 1.5; 95% CI: 0.9, 2.6). No data were collected on specific chemicals or brand names. These results raise new questions about the possible epidemiologic association of TGA with some classes of pesticides and warrant new, carefully targeted investigations.     

The contribution of maternal epilepsy and its treatment to the etiology of oral clefts: A population based case-control study

The associations between maternal epilepsy and anticonvulsant drug therapy with the risk of oral clefts in the offspring were investigated using data from a population-based case-control study. Cases included 238 infants with cleft lip ± cleft palate (CLP) and 107 infants with cleft palate (CP) ascertained through the Metropolitan Atlanta Congenital Defects Program (MACDP) between 1968 and 1980. Controls included 3029 population-based normal infants. Histories of maternal epilepsy and drug therapy during pregnancy were compared between cases and controls using maternal interviews and reviews of hospital medical records. Maternal epilepsy was associated with increased risk of nonsyndromic CLP (OR = 3.78, 95% C.I. 1.65–7.88), and less with CP (OR = 1.75, 95% C.I. 0.20–6.99). Therapy during pregnancy was associated with the greatest excess risk (CLP OR = 7.77, C.I. 2.02–26.0; CP OR = 3.61, C.I. 0.08–26.5). The use of polytherapy was associated with the highest risk (CLP OR = 10.5, C.I. 1.52–59.9). Adjustment for potential confounding variables in the study did not change these findings. In this well-defined population, maternal epilepsy and its treatment account for a small proportion of nonsyndromic oral clefts (attributable fraction CLP = 3.3%, CP = 0.9%). © 1994 Wiley-Liss, Inc.     

Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts

BACKGROUND: Smoking during pregnancy has been associated with orofacial clefts in numerous studies. However, most previous studies have not been able to assess the relation between maternal smoking and specific phenotypes (eg, bilateral clefts). METHODS: We examined the association between periconceptional maternal smoking, environmental tobacco smoke (ETS) exposure, and cleft lip with or without cleft palate (CLP) (n = 933) and cleft palate only (CPO) (n = 528) compared with infants with no major birth defects (n = 3390). Infants were born between 1 October 1997 and 31 December 2001, and exposures were ascertained from maternal telephone interviews for the National Birth Defects Prevention Study. We excluded infants who had a first-degree relative with an orofacial cleft. Effect estimates were adjusted for folic acid use, study site, prepregnancy obesity, alcohol use, gravidity, and maternal age, education, and race/ethnicity. RESULTS: Periconceptional smoking was associated with CLP (odds ratio = 1.3; 95% confidence interval = 1.0-1.6), and more strongly associated with bilateral CLP (1.7; 1.2-2.6), with a weaker association observed for CPO. Heavy maternal smoking (25+ cigarettes/day) was associated with CLP (1.8; 1.0-3.2), bilateral CLP (4.2; 1.7-10.3), and CPO with Pierre Robin sequence (2.5; 0.9-7.0). ETS exposure was not associated with CLP or CPO. CONCLUSIONS: This study confirmed the modest association between smoking and orofacial clefts that has been consistently reported, and identified specific phenotypes most strongly affected.     

Oral clefts and life style factors — A case-cohort study based on prospective Danish data

This study examines the association between oral clefts and first trimester maternal lifestyle factors based on prospective data from the Danish National Birth Cohort. The cohort includes approximately 100,000 pregnancies. In total 192 mothers gave birth to child with an oral cleft during 1997–2003. Information on risk factors such as smoking, alcohol consumption, tea, coffee, cola, and food supplements was obtained during pregnancy for these and 828 randomly selected controls. We found that first trimester maternal smoking was associated with an increased risk of oral clefts (odds ratio (OR): 1.50; 95% confidence interval (CIs): 1.05, 2.14). Although not statistically significant, we also saw associations with first trimester consumption of alcohol (OR: 1.11; CIs: 0.79, 1.55), tea (OR: 1.31; CIs: 0.93, 1.86), and drinking more than 1 l of cola per week (OR: 1.40; CIs: 0.92, 2.12). Furthermore supplementation with ≥400 mcg folic acid daily during the entire first trimester (OR: 0.75; CIs: 0.46, 1.22) suggested an inverse associated with oral clefts, similar to our results on coffee drinking. No effects were found for smaller doses of folic acid, vitamin A, B6 or B12 in this study. The present study found an association between oral clefts and smoking and, although not conclusive, supports an association of oral cleft with alcohol.